NutriNeuro

Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)gamma and tumor necrosis factor (TNF)alpha in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNgammaR(-/-) mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNgammaR(-/-) mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNgammaR(-/-) mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNgamma, interleukin(IL)-1beta, TNFalpha, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNgammaR(-/-) mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFalpha mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNgammaR(-/-) mice compared with WT controls. Pretreatment of mice with the TNFalpha antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNgamma and TNFalpha synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNgamma, with TNFalpha, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection.

Ageing of the global population has become a public health concern with an important socio-economic dimension. Ageing is characterized by an increase in the concentration of inflammatory markers in the bloodstream, a phenomenon that has been termed "inflammageing". The inflammatory response is beneficial as an acute, transient reaction to harmful conditions, facilitating the defense, repair, turnover and adaptation of many tissues. However, chronic and low grade inflammation is likely to be detrimental for many tissues and for normal functions. We provide an overview of low grade inflammation (LGI) and determine the potential drivers and the effects of the "inflamed" phenotype observed in the elderly. We discuss the role of gut microbiota and immune system crosstalk and the gut-brain axis. Then, we focus on major health complications associated with LGI in the elderly, including mental health and wellbeing, metabolic abnormalities and infections. Finally, we discuss the possibility of manipulating LGI in the elderly by nutritional interventions. We provide an overview of the evidence that exists in the elderly for omega-3 fatty acid, probiotic, prebiotic, antioxidant and polyphenol interventions as a means to influence LGI. We conclude that slowing, controlling or reversing LGI is likely to be an important way to prevent, or reduce the severity of, age-related functional decline and the onset of conditions affecting health and well-being; that there is evidence to support specific dietary interventions as a strategy to control LGI; and that a continued research focus on this field is warranted.

Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut–brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut–brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut–brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein.Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins

The incidence of depression and anxiety is amplified by obesity. Mounting evidence reveals that the psychiatric consequences of obesity stem from poor diet, inactivity, and visceral adipose accumulation. Resulting metabolic and vascular dysfunction, including inflammation, insulin and leptin resistance, and hypertension, have emerged as key risks to depression and anxiety development. Recent research advancements are exposing the important contribution of these different corollaries of obesity and their impact on neuroimmune status and the neural circuits controlling mood and emotional states. Along these lines, this review connects the clinical manifestations of depression and anxiety in obesity to our current understanding of the origins and biology of immunometabolic threats to central nervous system function and behavior.

Prenatal stress (PS) can cause early and long-term developmental effects resulting in part from altered maternal and/or fetal glucocorticoid exposure. The aim of the present study was to assess the impact of chronic restraint stress during late gestation on feto-placental unit physiology and function in embryonic (E) day 21 male rat fetuses. Chronic stress decreased body weight gain and food intake of the dams and increased their adrenal weight. In the placenta of PS rats, the expression of glucose transporter type 1 (GLUT1) was decreased, whereas GLUT3 and GLUT4 were slightly increased. Moreover, placental expression and activity of the glucocorticoid "barrier" enzyme 11beta-hydroxysteroid dehydrogenase type 2 was strongly reduced. At E21, PS fetuses exhibited decreased body, adrenal pancreas, and testis weights. These alterations were associated with reduced pancreatic beta-cell mass, plasma levels of glucose, growth hormone, and ACTH, whereas corticosterone, insulin, IGF-1, and CBG levels were unaffected. These data emphasize the impact of PS on both fetal growth and endocrine function as well as on placental physiology, suggesting that PS could program processes implied in adult biology and pathophysiology.

CONTEXT: Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. OBJECTIVES: To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. DESIGN: Cross-sectional and longitudinal studies. SETTING: Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. PATIENTS: Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. MAIN OUTCOME MEASURES: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity. RESULTS: Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. CONCLUSIONS: These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

Peripheral and central injections of interleukin-1 (IL-1) and lipopolysaccharide (LPS) induce the expression of proinflammatory cytokines in the brain and have profound depressing effects on spontaneous and learned behaviors. These effects are mediated by vagal afferents, because they are abrogated by section of the vagus nerves at the subdiaphragmatic level in rats and mice. Vagotomy does not interfere with the synthesis and release of proinflammatory cytokines at the periphery, because plasma and tissue levels of interleukin-1 of vagotomized animals are similar to those of sham-operated animals. Furthermore, the consequences of vagotomy on the host behavioral response to peripheral cytokines are specific to the intraperitoneal route of administration of cytokines because vagotomized animals are still able to respond to IL-1 injected intravenously, subcutaneously, and into the lateral ventricle of the brain. Finally, substance P and cholecystokinin do not appear to play a key role in the transmission of the immune message to the brain because pretreatment by capsaicin or by specific antagonists of CCKA and CCKB receptors does not alter the behavioral effects of LPS and IL-1. All these findings point to the role of neural afferents for transmitting the immune message from the periphery to the brain.

More than one-third of American adults are obese and statistics are similar worldwide. Caloric intake and diet composition have large and lasting effects on cognition and emotion, especially during critical periods in development, but the neural mechanisms for these effects are not well understood. A clear understanding of the cognitive-emotional processes underpinning desires to over-consume foods can assist more effective prevention and treatments of obesity. This review addresses recent work linking dietary fat intake and omega-3 polyunsaturated fatty acid dietary imbalance with inflammation in developing, adult, and aged brains. Thus, early-life diet and exposure to stress can lead to cognitive dysfunction throughout life and there is potential for early nutritional interventions (e.g., with essential micronutrients) for preventing these deficits. Likewise, acute consumption of a high-fat diet primes the hippocampus to produce a potentiated neuroinflammatory response to a mild immune challenge, causing memory deficits. Low dietary intake of omega-3 polyunsaturated fatty acids can also contribute to depression through its effects on endocannabinoid and inflammatory pathways in specific brain regions leading to synaptic phagocytosis by microglia in the hippocampus, contributing to memory loss. However, encouragingly, consumption of fruits and vegetables high in polyphenolics can prevent and even reverse age-related cognitive deficits by lowering oxidative stress and inflammation. Understanding relationships between diet, cognition, and emotion is necessary to uncover mechanisms involved in and strategies to prevent or attenuate comorbid neurological conditions in obese individuals.

Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels.

Peripheral and central injections of lipopolysaccharide (LPS), a cytokine inducer, and recombinant proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) induce sickness behavior in the form of reduced food intake and decreased social activities. Mechanisms of the behavioral effects of cytokines have been the subject of much investigation during the last 3 years. At the behavioral level, the profound depressing effects of cytokines on behavior are the expression of a highly organized motivational state. At the molecular level, sickness behavior is mediated by an inducible brain cytokine compartment that is activated by peripheral cytokines via neural afferent pathways. Centrally produced cytokines act on brain cytokine receptors that are similar to those characterized on peripheral immune and nonimmune cells, as demonstrated by pharmacologic experiments using cytokine receptor antagonists, neutralizing antibodies to specific subtypes of cytokine receptors, and gene targeting techniques. Evidence exists that different components of sickness behavior are mediated by different cytokines and that the relative importance of these cytokines is not the same in the peripheral and central cytokine compartments.

Allostatic load (AL) is a measure of overall physiological wear-and-tear over the life course, which could partially be the consequence of early life exposures. AL could allow a better understanding of the potential biological pathways playing a role in the construction of the social gradient in adult health. To explore the biological embedding hypothesis, we examined whether adverse childhood experiences (ACEs) are associated with elevated AL in midlife. We used imputed data on 3,782 women and 3,753 men of the National Child Development Study in Britain followed up seven times. ACEs were measured using prospective data collected at ages 7, 11, and 16. AL was operationalized using data from the biomedical survey collected at age 44 on 14 parameters representing four biological systems. We examined the role of adult health behaviors, body mass index (BMI), and socioeconomic status as potential mediators using a path analysis. ACEs were associated with higher AL for both men and women after adjustment for early life factors and childhood pathologies. The path analysis showed that the association between ACEs and AL was largely explained by early adult factors at age 23 and 33. For men, the total mediated effect was 59% (for two or more ACEs) via health behaviors, education level, and wealth. For women, the mediated effect represented 76% (for two or more ACEs) via smoking, BMI, education level, and wealth. Our results indicate that early psychosocial stress has an indirect lasting impact on physiological wear-and-tear via health behaviors, BMI, and socioeconomic factors in adulthood.

Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially modulate each other's functions. Importantly, microglia-mediated phagocytosis and inflammation are suppressed by infiltrating macrophages. In the context of spinal cord injury (SCI), preventing such communication increases microglial activation and worsens functional recovery. We suggest that macrophages entering the CNS provide a regulatory mechanism that controls acute and long-term microglia-mediated inflammation, which may drive damage in a variety of CNS conditions.

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.

Abstract. Stable isotope analysis is a powerful tool for assessing plant carbon and water relations and their impact on biogeochemical processes at different scales. Our process-based understanding of stable isotope signals, as well as technological developments, has progressed significantly, opening new frontiers in ecological and interdisciplinary research. This has promoted the broad utilisation of carbon, oxygen and hydrogen isotope applications to gain insight into plant carbon and water cycling and their interaction with the atmosphere and pedosphere. Here, we highlight specific areas of recent progress and new research challenges in plant carbon and water relations, using selected examples covering scales from the leaf to the regional scale. Further, we discuss strengths and limitations of recent technological developments and approaches and highlight new opportunities arising from unprecedented temporal and spatial resolution of stable isotope measurements.

Background: Obesity is a condition with a complex pathophysiology characterized by both chronic low-grade inflammation and changes in the gut microbial ecosystem. These alterations can affect the metabolism of tryptophan (TRP), an essential amino acid and precursor of serotonin (5-HT), kynurenine (KYN) and indoles. This study aimed to investigate alterations in KYN and microbiota-mediated indole routes of TRP metabolism in obese subjects relatively to non-obese controls and to determine their relationship with systemic inflammation. Methods: Eighty-five obese adults (avg. BMI=40.48) and forty-two non-obese control individuals (avg. BMI=24.03) were recruited. Plasma levels of TRP catabolites were assessed using Ultra High Performance Liquid Chromatography-ElectroSpray-Ionization-Tandem Mass Spectrometry. High-sensitive C-reactive protein (hsCRP) and high-sensitive interleukin 6 (hsIL-6) were measured in the serum as markers of systemic inflammation using enzyme-linked immunosorbent assay. Results: Both KYN and microbiota-mediated indole routes of TRP metabolism were altered in obese subjects, as reflected in higher KYN/TRP ratio and lower 5-HT and indoles levels, relatively to non-obese controls. HsIL-6 and hsCRP were increased in obesity and were overall associated with TRP metabolic pathways alterations. Conclusion: These results indicate for the first time that KYN and indole TRP metabolic pathways are concomitantly altered in obese subjects and highlight their respective associations with obesity-related systemic inflammation.

Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1β and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.

Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.

Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.

To examine the role of tumor necrosis factor-alpha (TNF alpha) in mediating leptin secretion during an immunological challenge, we studied the effects of lipopolysaccharide (LPS) and TNF alpha on leptin secretion in endotoxin-sensitive C3H/HeOuJ (OuJ) mice, endotoxin-insensitive C3H/HeJ (HeJ) mice, and primary adipocytes cultured from both. Intraperitoneal injection of LPS increased plasma concentrations of TNF alpha and leptin in OuJ mice, but not in HeJ mice, suggesting a causal relationship between the induction of TNF alpha and leptin. Consistent with this idea, i.p. injection of recombinant murine TNF alpha increased plasma leptin in both OuJ and HeJ mice. To determine whether TNF alpha induces leptin secretion by acting directly on fat cells, primary adipocytes from OuJ and HeJ mice were cultured in the presence of TNF alpha or LPS. Whereas LPS was without effect on leptin secretion by adipocytes, TNF alpha induced a marked increase in the cell supernatant leptin concentration. These data demonstrate that TNF alpha plays a role in regulating the increase in leptin caused by LPS. Moreover, they show that TNF alpha can act directly on adipocytes to stimulate leptin secretion. Our results are consistent with the emerging view that leptin is a key hormone coupling immune system activity to energy balance.